Mecurated biuret derivatives



and their manufacture.

- or lower alkyl, e. g. methyl, ethyl and the like.

MECURATED BIURET DERIVATIVES Lincoln Harvey Werner, Summit, NJ., assignor to Ciba Pharmaceutical Products, Inc., Summit, N .J a corporation. of New Jersey No Drawing. Application March 29, 1955 Serial No. 497,792

11 Claims. (Cl. 260 -242) This invention relates to mercurated biuret derivatives More particularly the invention relates to allyl biuret compounds having the structural formula:

(I? (I'I) R1 RNHONHCNHCHzHOHzHgOH and salts thereof, wherein R and R represent hydrogen As salts, there are contemplated especially those with inorganic acids or organic carboxylic acids, for example hydrohalic benzoic or salicylic acid and the like, or'theophylline.

The invention is especially concerned with 1-3-hydroxymercuri-Z-methoxy-propyl)-biuret and its salts.

The compounds of the invention in general are prepared by reacting the appropriate mercuric salt such as mercuric chloride, mercuric acetate and the like, or mercuric oxide in the presence of the appropriate acid, with an allyl biuret of the formula:

II II RNHCNHCNHCHn-CH=CH2 wherein R has the aforesaid meaning. The mercuration reaction is carried out in water or lower alkanols, e.g. methanol or ethanol, or mixtures of the two. The mercuration may be carried out at room temperature or at elevated temperatures, such as those produced by a steam bath. If necessary, alkali is added to the reaction mixture to bind strong acids set free during the reaction.

Depending on the nature of the solvent used, compounds are obtained which carry in Z-position a free hydroxy group or a hydroxy group etherified with a lower alkanol.

Depending on the working conditions, the new compounds are obtained in the form of the free hydroxybases or salts thereof. From the salts the hydroxy compounds can be obtained, for example by treatment with alkali. The free bases can be converted into their therapeutically useful or non-toxic salts by reaction with the appropriate acids. converted into other salts by double decomposition. Thus, an acetate may be converted into a bromide by reaction with sodium bromide.

The allyl biurets used as starting materials are in general prepared by heating a nitro biuret with allyl amine in aqueous solution according to the procedure:

Alternatively allyl biurets are prepared by heating allyl.

RNniiNHooooHs H:NCH:CH=OH:' 1

wherein R has the meanings as aforesaid.

Furthermore, salts obtained may be United States Patent 1 2,880,206 Patented Mar. 31, 1959 ice -They are active When given parenterally and are of especial interest by virtue of a strong diuretic activity when administered orally. l-(3-hydroxymercuri-2-methoxy-propyl)-biuret; shows outstanding activity when administered orally.

For therapeutical use the new compounds may be made up into pharmaceutical compositions together with a pharmaceutical carrier. These compositions may be in any suitable solid or liquid dosage form, especially in a form suitable for oral or parenteral administration, e.g. tablets, capsules, pills or solutions, e.g. in the form of ampouled injectable-solutions. As pharmaceutical carriers, there may be employed materials or mixtures of such which do not react withthe new compounds and are therapeutically useful. Substances or mixtures thereof, such as water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, ascorbic acid, gums, glycols such as propylene glycol or polyalkylene glycol, petroleum jelly, cholestero, tragacanth, alcohol or others may be employed. In preparing the novel compositions, the new compounds are admixed with the pharmaceutical'carrier and formulated in the desired dosage unit form according to pharmaceutical practice. The compositions may be sterilized and may contain auxiliary substances, such as preservatives, stabilizing,

wetting or emulsifying substances, salts for the control of the osmotic pressure or buffer substances or other therapeutically active substances.

This application is a continuation-in-part application of my copending application, Serial No. 426,579, filed April 29, 1954, now abandoned.

The invention is illustrated in greater detail in the examples which follow. It is to be understood that these examples are presented by way of illustration and not of limitation. Temperatures are uncorrected and are expressed in degree of centigrade. Parts by weight bear the same relation to parts by volume as do grams to milliliters.

' Example I parts by weight of nitro biuret, 21 parts by weight of allyl amine and 150 parts by volume of water are mixed and heated gently on a steam bath so that the evolution of nitrous oxide does not become too vigorous. v When the evolution of gas slows down, the temperature of the reaction mixture is gradually raised until the evomixed and heated on the steam bath for /2 hour. After standing at room temperature for 1 hour, the mixture, containing the acetate of 1-(3-hydroxymercuri-Z-methoxypropyD-biuret, is filtered. 78 parts by volume of l N methanolic sodium hydroxide are added to the filtrate and the white solid which precipitates is filtered 0E. The solid residue thus obtained is reprecipitated by dissolving in 1.9 parts by .volumeof .acetic acid .and .50 parts by volume of methanol followed by the addition of 34 parts by volume of l N methanolic sodium hydroxide. The

mixture is then filtrated to "yield l-(3-hydroxymercuri-2- methoxy-propyD-biuret; M.P. "-170 (dec.) and 'having the formula:

.times with ethyl acetate.

- permitted to stand at room temperature for 1 hour.

3 Example 2 I A solution of 1.43 parts by weight of l-allyl-biuret dissolved in 30 parts by volume of methanol and a solution of 3.18 parts by weight of mercuric acetate dissolved in 60 parts by volume of methanol are combined and heated for 15 minutes on a steam bath. The mixture is filtered 2-methoxy-propyD-biuret, is filtered off, washed with water, dried and recrystallized from methanol; MP. -170-- 173.

It has the formula:

OCH: HZNiiNmiNHCHmHGHZH CI Bysubstituting a saturated solution containing an equivalent quantity of sodium bromide for the sodium.chloride, the bromide of l-(3-hydroxymercuri-2methoxypropyl)-biuret is obtained.

Example 3 12.8 parts by Weight of N-ethyl-allophanic acid methyl ester, 17 parts by volume of allyl amine and 33 parts by volume of water are mixed, sealed in a reaction tube and heated at 100 for 2 hours. After cooling, the solution is removed, evaporated to dryness and extracted three The ethyl acetate extract is dried over sodium sulfate, filtered and the filtrate concentrated and chilled. The crystalline product which separates is recrystallized from water to yield 1-allyl-5-ethylbiuret melting at 7780.

1.93 parts by weight .of l-allyl-S-ethyl-biuret dissolved in 50 parts by volume of methanol are added to a solution of 4.2 parts by weight of mercuric acetate in 50 parts by volume of methanol. The mixture is heated on the steam bath for /2 hour after which it is allowed to stand at room temperature for an additional hour. The mixture is then filteredand evaporated .to dryness in vacuo whereupon the acetate of l-(3-hydroxyrnercuri-2- methoxy-propyl)--ethyl-biuret is obtained as a water soluble syrup having the formula:

H H 0 CH3 CzHsNHCNHCNHCHzCHCH2HgOC 0 011a Example 4 A solution of parts by volume of allyl amine dissolved in 15 parts by volume of water is added to 6.4 parts by weight of methyl allophanic. acid methyl ester and the mixture heated at 100 for three hours in a sealed reaction tube. After cooling to room temperature, the solution is concentrated and allowed to stand. The crystals which separate are recrystallized from water to yield l-allyl-S-methyl-biuret; M.P. 107-109.

A solution of 1 part by weight of l-allyl-S-methylbiuret in 10 parts by volume of methanol is added to a solution of 2.02 parts by weight of mercuric acetate dissolved in 25 parts by volume of methanol. The mixture is heated for 6. hour on the steam bath after which it is The reaction mixture is filtered and concentrated to dryness to yield the acetate of l-(3-hydroxymercuri-2-methoxypropyl)-S-methyl-biuret as a water soluble syrup having the formula:

t t CHaNHCNHCNHCHaCH'CHHgOC0*CH:

.Example 5 1.96 parts by weight of l-(3-hydroxymercuri-2-methr oxy-propyl)-biuret is added to a solution of 0.91 part by the filtrate"evaporated to dryness. Acetone is 'a'ddedand the powdery product filtered off; M.P. 140-l60 (dec.).

The theophylline-salt of 1-(3-hydroxymercuri-Z-methoxypropyl)-biuret has the formula:

A solution of 6.0 parts by weight mercuric acetate in parts by Volume waterzand 0.1 part by volume of acetic acid is added to 2.86 parts by Weight l-allyl-biuret dissolved in 30 parts by volumewater, the reaction mixture warmed on the steambath for 30 minutes and then allowedto'standat room temperature for 3 hours. The solution is filtered and made alkaline'by adding 2-normal potassium -'carbonate.

A: precipitate forms which is washed with water and methanol, filtered off and dried. The product is dissolved in 60 parts by volume of methanol and 5.0 parts by .volume acetic acid, the solution filtered, neutralized with methanolic normal sodium hydroxide and the precipitate which forms is filtered off,

washed with methanol and dried in vacuo. The product,

1-(3-hydroxymercuri-2-hydroxy-propyl)-biuret; melts with "decomposition at 160 and corresponds to the'formula:

t t HzNONHCNHOHzCHCHzHgNO;

is obtained. It is soluble in water and melts with foaming at 129.

Example 8 4.3 g. l-allylbiuret are dissolved in 60 ml. methanol at 50 and 6.5 g. mercuric oxide are added. With agitation 15 ml. 2 'N nitric acid are added dropwise. After 10 minutes almost all mercuric oxide dissolves. The solution is filtered and allowed to stand at room temperature. After several hours the nitrate of 1-(3-hydroxymercuri-2- methoxy-propyl)-biuret begins to crystallize. After standing for one to two days, the product is filtered off, washed with methanol and dried. It is water soluble and melts with foaming at 129.

Instead of isolating the mercurated allylbiuret as the nitrate, the aqueous methanol solution can be treated with methanolic sodium hydroxide to yield the 1-(3-hydroxymercuri 2 methoxy) biuret as described in Example 1.

Example 9 3.92 g. 1-3-hydroxymercuri-2-methoxy-propyl)-biuret is suspended in 20 ml. methanol and 10 ml. sulfuric acid is added. The hydroxymercuri compound dissolves to form the sulfate. The solution is evaporated to dryness and the residue triturated with alcohol and acetone. The product, the sulfate of 1-(3-hydroxymercuri-2methoxypropyl)-biuret of the formula:

. is filteredofi and dried in vacuo. It is soluble in water and melts with foaming at 97.

Example 10 1.95 g. 1-(3-hydroxymercuri-2-methoxy-propyl)-biuret, 0.73 g. glutamic acid and 65 ml. water are mixed and stirred. The resulting clear solution is evaporated to dryness. The residue is triturated with acetone and ether and dried in vacuo. The thus obtained glutamate of 1 (3 hydroxy mercuri 2 methoxy propyl)- biuret melts at 110-120.

Example 11 3.92 g. 1-(3-hydroxymercuri-2-methoxy-propyl)-biuret, 1.22 g. benzoic acid and 20 ml. methanol are combined. On standing and stirring, a clear solution is obtained, which is evaporated to dryness. The solid residue is triturated with ether and filtered off. The benzoate of l-(3-hydroxymercuri-Z-methoxy-propyl)-biuret forms a white powder which is only slightly soluble in water and melts with foaming at 75. It has the formula:

3 OCH: NHjCNHNHCHiCHCHQHEOC0-ClHi Example 12 3.92 g. 1-(3-hydroxymercuri-2-methoxy-propyl)-biuret, 1.38 g. salicylic acid and 20 ml. methanol are combined. On stirring a clear solution results which is evaporated to dryness and the residue triturated with ether and filtered ofi and dried in vacuo. The thus obtained salicylate of 1 (3 hydroxymercuri 2 methoxypropyl)-biuret is slightly soluble in water and melts with foaming at 130. It has the formula:

i 1? umormcmromoncmmoooQ Example 13 1-(3-hydroxymercuri-Z-methoxy-propyl)-biuret can be made up into pharmaceutical preparations, for example For this purpose, the lactose, tragacanth and mercuri compound are screened using a No. screen and mixed.

The mixture is granulated with percent 3A alcohol, passed through a square hole screen and dried at room temperature. After passing through a No. 3 screen, the mixture is used for compressing 200 mg. tablets.

What is claimed is:

1. Compounds of the group consisting of organic mercury compounds of the formula:

wherein R and R represent members selected from the group consisting of hydrogen and lower alkyl, and therapeutically useful salts of the mercury base with an acid.

2. 1-(3-hydroxymercuri-Z-methoxy-propyl)-biuret.

3. The acetate of 1-(3-hydroxymercuri-Z-methoxypropyl)-biuret.

4. The chloride of 1-(3-hydroxymerciuri-Z-methoxypropyl)-biuret.

5. The bromide of 1-(3-hydroxymercuri-2-methoxypropyl)-biuret.

6. 1 (3 hydroxymercuri 2 methoxy propyl) 5- ethyl-biuret.

7. The acetate of 1-(3-hydroxymercuri-2-methoxypropyl)-S-ethyl-biuret.

8. 1 (3 hydroxymercuri 2 methoxy propyl) 5- methyl-biuret.

9. The acetate of 1-(3-hydroxymercuri-Z-methoxypropyl)-S-methyl-biuret.

10. 1 (3 hydroxymercuri 2 hydroxy propyl)- biuret.

11. The theophylline salt of 1-(3-hydroxymercuri-2- methoxy-propyl)-biuret.

References Cited in the file of this patent UNITED STATES PATENTS 2,145,392 Harmon Ian. 31, 1939 2,281,559 DAlelio May 5, 1942 2,378,110 Simons et al. June 12, 1945 2,576,349 Lehman Nov. 27, 1951 2,675,388 Lehman Apr. 13, 1954 FOREIGN PATENTS 974,085 France Sept. 27, 1950 4,250 Great Britain Aug. 22, 1907 165,779 Great Britain Apr. 13, 1922 OTHER REFERENCES Jour. Org. Chem., vol. 15, pages 1055-1059 (1950).

Rowland et al.: J. A. C. S., 72, 3595-97 (August 1950).

Rowland et al.: J. A. C. S., 73, 3691-3693 (January 1951).

i Attest:

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,880,206 March 31, 1959 Lincoln Harvey Werner 7 It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below. 7

Column 1, lines 30 and 31, for 1-3-hydroxymercuriread 1-(3-hydroxymercuri-; same column, last line, for Wherein R has the meanings read Wherein R has the meanings; column 2, line 20, for cholestero read cholesterol; column 4, line 64, for 1-3-hydroxymercuriread 1-(3-hydroxymercuri-; same column 4:, Example 9, the formula should read as shown below instead of as in the patent:

. 0 o eon,

HmiiNHliNHomcHomm sm Signed and sealed this 28th day of July 1959.

ROBERT C. WATSON, Conmz'ssioner of Patents.

KARL H. AXLINE, Attesting Ofiicer. 

1. COMPOUNDS OF THE GROUP CONSISTING OF ORGANIC MERCURY COMPOUNDS OF THE FORMULA:
 11. THE THEOPHYLINE SALT OF 1-(3-HYDROXYMERCURI-2METHOXY-PROPYL)-BIURET. 